Homeostatic Role and Therapeutic Potential of the Neuroprotective Retinal Lipoxin Circuit

神经保护性视网膜脂氧素回路的稳态作用和治疗潜力

• 批准号: 10115740
• 负责人: JOHN G FLANAGAN
• 金额: $ 46.39万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10115740
• 关键词: Acute; Affect; American; Astrocytes; Biological Assay; Blindness; Cell Death; Cell Survival; Cell physiology; Cells; Chronic; Clinical; Complex; Disease; Drug Targeting; Etiology; FPR2 gene; Family; Glaucoma; Goals; Health; Healthcare Systems; Homeostasis; Human; In Vitro; Inflammation; Inflammatory; Injury; LOX gene; Lead; Lipids; Lipoxin Receptors; Lipoxins; Mediating; Mediator of activation protein; Methods; Mitochondria; Modeling; Molecular; Muller' s cell; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuropathy; Neuroprotective Agents; Optic Disk; Optic Nerve; Paracrine Communication; Pathogenesis; Pathway interactions; Pharmacology; Phenotype; Physiologic Intraocular Pressure; Regulation; Research; Research Project Grants; Rest; Retina; Retinal Degeneration; Retinal Diseases; Retinal Ganglion Cells; Role; Signal Transduction; Stress; Stretching; Structure; Testing; Therapeutic; Tissues; Treatment Efficacy; Treatment Protocols; Vascular Endothelial Cell; adeno-associated viral vector; analog; base; biological adaptation to stress; experimental study; gene therapy; in vivo; insight; lipid mediator; lipidomics; lipoxin A4; lipoxin B4; liquid chromatography mass spectrometry; metabolomics; mouse model; neuroprotection; neurotoxic; neurotransmission; neurovascular; novel; optic nerve disorder; prevent; programs; receptor; relating to nervous system; response; response to injury; retinal ganglion cell degeneration; screening; selective expression; therapeutic target; transplant model

Project Summary/Abstract Glaucoma is a chronic degeneration of the retina and optic nerve, and a leading cause of irreversible blindness, estimated to afflict 80 million people worldwide. It is also the most common neurodegenerative disease in the world, affecting ~3 million Americans with an estimated $2.9 billion annual burden to the US Health Care system. Our understanding of the etiology and molecular mechanisms that drive the pathogenesis of glaucoma remain incomplete. Primary treatment options are limited to lowering intraocular pressure (IOP). There are no neuroprotective therapies to prevent or rescue the degenerative cascades that define glaucoma. Astrocytes are a central driver of structural and parainflammatory changes at the optic nerve head (ONH) and subsequent, irreversible retinal ganglion cells (RGC) death. Emerging evidence indicates that astrocytes have neuroprotective and pro-survival activities in glaucoma. The nature and relevance of these protective signals remains unclear. We recently identified a secreted neuroprotective activity in resting retinal astrocytes, which proved to be a previously unknown resident retinal lipoxin lipid mediator circuit. Lipoxins are a family of potent specialized proresolving lipid mediators (SPMs), which are being developed as drug targets due to their established role in dampening and resolving local inflammation in other tissues. We discovered that two lipoxins, LXA4 and LXB4, are generated by resting astrocytes and in the healthy retina and OHN and that a lipoxin receptor is selectively expressed in RGCs, which identified a previously unknown direct neural activity of lipoxins. This intrinsic pathway is dysregulated in response to retinal/ONH stress. More importantly, we established that therapeutic treatment with lipoxins is neuroprotective by increasing RGC survival and rescuing RGC function in both an acute neurotoxic retinal injury model, and a chronic IOP dependent model of glaucoma like neurodegeneration. We hypothesize that the lipoxin circuit is an important paracrine signaling mechanism to maintain neuronal homeostasis and protect the retina against stress. In a multiple-PI Research Project, we will characterize this novel neuroprotective network, define its mechanism of action and explore the efficacy of amplifying the lipoxin circuit as a therapeutic target for neuroprotection with the following three specific aims: 1) Characterize the mechanism of LXA4 and LXB4 formation in retina, ON, and astrocytes in the context of health and glaucomatous injury, 2) Define the distinct mechanisms of action for LXA4 and LXB4 pro- survival signaling in RGCs, and 3) Investigate the therapeutic potential of amplifying lipoxin circuits to prevent and/or stop RGC degeneration. This goal of this project is to generate transformative insights into a novel neuronal support mechanism and its dysregulation following injury or stress. Most importantly, we will test if amplification of this protective circuit can prevent or stop retinal/optic nerve degeneration and vision loss.

项目摘要/摘要 青光眼是视网膜和视神经的慢性变性，也是不可逆的主要原因 失明，估计在全球范围内折磨8000万人。它也是最常见的神经退行性 世界上的疾病，影响约300万美国人，估计对美国的每年29亿美元负担 医疗保健系统。我们对驱动发病机理的病因和分子机制的理解 青光眼仍然不完整。主要的治疗选择仅限于降低眼内压（IOP）。 没有神经保护疗法可以预防或拯救定义青光眼的退化性级联反应。 星形胶质细胞是视神经头（ONH）和 随后，不可逆的视网膜神经节细胞（RGC）死亡。新兴证据表明星形胶质细胞具有 青光眼中的神经保护作用和促生物活性。这些保护信号的性质和相关性 仍然不清楚。我们最近在静息视网膜星形胶质细胞中确定了一种分泌的神经保护活性，该活动 事实证明是以前未知的居民视网膜脂蛋白脂质介质电路。脂毒素是一个有力的家族 专门的促进脂质介质（SPM），由于其药物靶标而开发 确定在抑制和解决其他组织中局部炎症的作用。我们发现两个 脂毒素，LXA4和LXB4是通过静止的星形胶质细胞以及健康的视网膜和OHN产生的 LIPOXIN受体在RGC中选择性表达，该脂蛋白受体鉴定了先前未知的直接神经活动 脂蛋白。该内在途径因视网膜/ONH应激而失调。更重要的是，我们 确定通过增加RGC存活和救援，用脂毒素治疗具有神经保护作用 RGC在急性神经毒性的视网膜损伤模型和慢性IOP依赖模型中均功能 像神经退行性的青光眼。我们假设Lipoxin电路是重要的旁分泌信号 维持神经元体内平衡并保护视网膜免受压力的机制。在多个PI研究中 项目，我们将表征这个新颖的神经保护网络，定义其作用机理并探索 扩增脂毒素回路作为神经保护的治疗靶点的功效，以下三个 具体目的：1）表征视网膜上LXA4和LXB4形成的机理，ON和星形胶质细胞 健康和青光眼损伤的背景，2）定义LXA4和LXB4 Pro-的不同作用机理 RGC中的生存信号传导，以及3）研究扩增脂肪毒素回路的治疗潜力以防止 和/或停止RGC变性。这个项目的这个目标是将变革性见解成为小说 受伤或压力后神经元支持机制及其失调。最重要的是，我们将测试是否 该防护电路的扩增可以预防或阻止视网膜/视神经退化和视力丧失。